Two challenges in the area of biomarkers of PD and related disorders are validating indices of central dopamine (DA) deficiency and distinguishing PD from multiple system atrophy (MSA). We completed a study on these issues, comparing efficiencies of several potential biomarkers. In PD, MSA, and control subjects, radioactivity concentrations in the putamen (PUT), caudate (CAU), occipital cortex (OCC), and substantia nigra (SN) were measured 2 hours after 6-18F-fluorodopa injection, septal myocardial radioactivity measured 8 minutes after 6-18F-fluorodopamine injection, cerebrospinal fluid (CSF) and plasma catechols assayed, or olfaction tested (University of Pennsylvania Smell Identification Test (UPSIT)). Receiver operating characteristic curves were constructed, showing test sensitivities at given specificities. PUT:OCC, CAU:OCC, and SN:OCC ratios of 6-18F-fluorodopa-derived radioactivity were similarly low in PD and MSA, as were CSF dihydroxyphenylacetic acid (DOPAC) and DOPA concentrations. PUT:SN and PUT:CAU ratios were lower in PD than in MSA. CSF DOPAC correlated positively with PUT:OCC ratios (r=0.61, p<0.0001). Myocardial 6-18F-fluorodopamine-derived radioactivity distinguished PD from MSA (83% sensitivity at 80% specificity, 100% sensitivity among patients with neurogenic orthostatic hypotension). Only PD patients have no sense of smell; only MSA patients had normal olfaction (61% sensitivity at 80% specificity). PD and MSA therefore feature low PUT:OCC ratios of 6-18F-fluorodopa-derived radioactivity and low CSF DOPAC and DOPA concentrations, cross-validating the neuroimaging and neurochemical biomarkers but not distinguishing the diseases; and PUT:SN and PUT:OCC ratios of 6-18F-fluorodopa-derived radioactivity, cardiac 6-18F-fluorodopamine-derived radioactivity, and olfactory testing can separate PD from MSA[unreadable] [unreadable] We are pursuing the above findings, by determining which biomarkers of central DA deficiency or distinguishing PD from MSA are abnormal early in the diseases or in pre-symptomatic individuals. We are adding liquid chromatography with tandem mass spectroscopy (LC/MS/MS) to the repertoire of clinical laboratory tests available in the CNCS, to identify patterns of pathogenetically relevant neurochemical abnormalities.